Burzynski Stanislaw R
Burzynski Clinic, 9432 Old Katy Road, Houston, TX 77055, USA.
Med Hypotheses. 2005;64(1):201-8. doi: 10.1016/j.mehy.2004.06.010.
According to the author's theory of gene silencing, the key process in aging involves reduced expression of a number of genes. Silencing of genes has a complex mechanism, which involves methylation of DNA, histone modification and chromatin remodeling. In addition to deacetylation of the histones and methylation of DNA, recently described RNAi mechanism could initiate formation of silenced chromatin. Hypermethylation of the promoter will silence the gene. Genome-wide hypomethylation will induce genomic instability, amplification of oncogenes and also silencing of the genes through RNAi mechanism. Studies by different groups, conducted in yeast, worms, flies and mice, confirmed substantial changes in gene expression in aging. Among them, the most important was silencing of tumor suppressors and other genes involved in the control of cell cycle, apoptosis, detoxification, and cholesterol metabolism. There was also increased expression of the smaller group of oncogenes and other genes which are associated with typical diseases of old age. Caloric restriction normalizes expression of a substantial percentage of these genes. Animal studies confirmed importance of caloric restriction, which decreases signaling through the IGF-1/AKT pathway and expression of gene p53. These studies, however, cannot be directly applied to human aging. It is proposed that age management therapy should attempt to normalize gene expression in the older population to the level typical for young adults. This would require activation of silenced genes and normalization of overexpressed genes. Caloric restriction and exercise are helpful in decreasing the activity of important oncogenes and activation of silenced tumor suppressors, and may have a positive impact, not only on aging, but also on prevention of cancer. Dietary supplements containing phytochemicals should normalize increased expression of oncogenes. Examples are: genistein and EGCG, which effect signaling through the IGF-1/AKT pathway and resveratrol and limonen, which do so through the RAS pathway. A group of amino acid derivatives and organic acids of animal and human origin should activate silenced tumor suppressor genes (Aminocare A10, Aminocare Extra). Among them 3-phenylacetylamino-2, 6-piperidinedione intercalates specifically with DNA and protects sequences of tumor suppressor genes, which are vulnerable to the effects of carcinogens. Phenylacetate activates p53 and p21 through inhibition of methyltransferase and farnesylation of the RAS protein. Phenylbutyrate activates tumor suppressor genes through inhibition of histone deacetylation. Phenylacetylglutamine decreases genomic instability and expression of oncogenes and promotes apoptosis. The application of DNA microarray techniques to human studies should provide more information about differences in gene expression in different age groups and help design more effective age management regimens.
根据作者的基因沉默理论，衰老的关键过程涉及许多基因的表达减少。基因沉默具有复杂的机制，包括DNA甲基化、组蛋白修饰和染色质重塑。除了组蛋白去乙酰化和DNA甲基化外，最近描述的RNAi机制也可引发沉默染色质的形成。启动子的高甲基化会使基因沉默。全基因组低甲基化会诱导基因组不稳定、癌基因扩增，并通过RNAi机制使基因沉默。不同研究小组在酵母、蠕虫、果蝇和小鼠中进行的研究证实了衰老过程中基因表达的显著变化。其中，最重要的是肿瘤抑制基因和其他参与细胞周期控制、细胞凋亡、解毒及胆固醇代谢的基因的沉默。与老年典型疾病相关的一小部分癌基因和其他基因的表达也有所增加。热量限制可使这些基因中的很大一部分表达恢复正常。动物研究证实了热量限制的重要性，它可减少通过IGF-1/AKT途径的信号传导以及基因p53的表达。然而，这些研究不能直接应用于人类衰老。有人提出，年龄管理疗法应试图使老年人群的基因表达恢复到年轻人的典型水平。这需要激活沉默的基因并使过度表达的基因恢复正常。热量限制和运动有助于降低重要癌基因的活性并激活沉默的肿瘤抑制基因，不仅可能对衰老产生积极影响，还可能对癌症预防产生积极影响。含有植物化学物质的膳食补充剂应使癌基因增加的表达恢复正常。例如：染料木黄酮和表没食子儿茶素没食子酸酯通过IGF-1/AKT途径影响信号传导，白藜芦醇和柠檬烯则通过RAS途径发挥作用。一组动物和人类来源的氨基酸衍生物和有机酸应能激活沉默的肿瘤抑制基因（氨基关怀A10、氨基关怀增强型）。其中，3-苯乙酰氨基-2,6-哌啶二酮可与DNA特异性结合，并保护易受致癌物影响的肿瘤抑制基因序列。苯乙酸通过抑制甲基转移酶和RAS蛋白的法尼基化激活p53和p21。苯丁酸钠通过抑制组蛋白去乙酰化激活肿瘤抑制基因。苯乙酰谷氨酰胺可降低基因组不稳定性和癌基因表达，并促进细胞凋亡。将DNA微阵列技术应用于人体研究应能提供更多关于不同年龄组基因表达差异的信息，并有助于设计更有效的年龄管理方案。
